The present invention relates to a series of new steroid derivatives which have the ability to inhibit the activity or effects of testosterone 5.alpha.-reductase, and can thus be used for the treatment or prophylaxis of prostatic hypertrophy. The invention also provides methods and compositions using these new compounds, as well as processes for preparing them.
Testosterone is an active hormone produced in the male by the testes. It may be reduced by 5.alpha.-reductase to 5.alpha.-dihydrotestosterone, which is active, inter alia, in the prostate.
High levels of 5.alpha.-dihydrotestosterone have been implicated in a number of disorders, including prostatic enlargement, acne, male pattern baldness and female hirsutism. Enlargement of the prostate, otherwise known as "prostatic hypertrophy", is an age-related, progressive disease, which afflicts a high proportion of men over 50 years of age. Since it can result in impaired urinary function, it is generally dealt with by surgery, which itself has undesired side effects, including sterility. In an effort to avoid this, attempts have been made to develop drugs which will prevent or treat the condition. Although success has been achieved by the administration of so-called "anti-androgens", such as the oestrogens or derivatives thereof, these have resulted in side effects, such as feminisation, which many men presently consider undesirable.
There is, therefore, a need for a drug capable of treating or preventing prostatic hypertrophy without the feminising effects of the anti-androgens.
The other effects of high levels of 5.alpha.-dihydrotestosterone, that is acne, male pattern baldness and female hirsutism, are not medically serious, but are very distressing for the sufferers, and no reliable therapy is currently available.
Since the 5.alpha.-reductase inhibitors do not inhibit the activity of testosterone, it was postulated that they might provide the required activity, and a number of such compounds have been developed which demonstrate the accuracy of this hypothesis.
For example, European Patent Publications No. 4949 and 155 096 disclose some androstane derivatives which are claimed to have 5.alpha.-reductase inhibitory activity. These, however, differ from the compounds of the present invention in that they have a heterocyclic ring for the so-called "A-ring" of the steroid moiety, in place of the carbocyclic ring of the present compounds.
The closest prior art is believed to be the compounds described in European Patent Publication No. 289 327 and in J. Med. Chem., 33, 943-950 (1990), especially at page 945, and in Biochemistry, 29, 2815-2824 (1990), all of which disclose the compounds hereinafter referred to as Compounds A and B, which are 17.beta.-(diisopropylcarbamoyl)androsta-3,5-diene-3-carboxylic acid and 17.beta.-t-butylcarbamoylandrosta-3,5-diene-3-carboxylic acid, respectively, which have the formulae (A) and (B), respectively: ##STR2## Of these, the t-butyl compound, Compound B, is thought to have the best balance of activities, toxicity and usefulness and is currently under investigation, and now in Phase III, as a potential commercial drug.